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Topamax

Generic Name: Topiramate
Class: Anticonvulsants, Miscellaneous
VA Class: CN400
Chemical Name: 2,3:4,5-bis-O-(1-Methylethylidene)-β-d-fructopyranose sulfamate
Molecular Formula: C12H21NO8S
CAS Number: 97240-79-4

Introduction

Anticonvulsant and antimigraine agent; sulfamate-substituted derivative of d-fructose;1 2 3 4 5 17 18 differs structurally from other currently available anticonvulsant agents.1 2 3 4 5 17 18

Uses for Topamax

Seizure Disorders

Initial monotherapy of partial seizures or primary generalized tonic-clonic seizures in adults and children ≥2 years of age.1 51 Safety and efficacy of topiramate monotherapy in previously treated patients not established.1

Management (in combination with other anticonvulsants) of partial seizures in adults and children 2–16 years of age.1 2 4 5 6 7 8 9 10 22 25 29 30 31 32 33 34 37 38

Management (in combination with other anticonvulsants) of primary generalized tonic-clonic seizures in adults and children ≥2 years of age.1 30 31 39

Management (in combination with other anticonvulsants) of seizures associated with Lennox-Gastaut syndrome in adults and children ≥2 years of age.1

Migraine Prophylaxis

Prophylaxis of migraine headache in adults.1 44 84

Efficacy in the acute treatment of migraine headache not established.1

Alcohol Dependence

Has been used in adults for management of alcohol dependence.52 53 54 55 56 57 60 61 62 73 74 75 76 77 78

One of several drugs recommended by the National Institute of Alcohol Abuse and Alcoholism (NIAAA) for this use.78 However, additional studies needed to more clearly establish role.53 57 60 61 65 74 75 78

Has been effective in the management of alcohol withdrawal in a limited number of patients in uncontrolled studies.61 65 66 76

Topamax Dosage and Administration

General

  • Monitoring of plasma topiramate concentrations is not necessary for optimizing anticonvulsive therapy.1

  • Addition of topiramate to phenytoin therapy may require adjustment of phenytoin dosage.1 Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy may require adjustment of topiramate dosage.1 2 4 11 (See Specific Drugs under Interactions.)

  • Adjust dosage carefully and individualize according to patient response and tolerance.1 2 4

  • Too rapid titration (e.g., over 3–6 weeks) to achieve target dosage and/or excessive target dosage may contribute to a higher incidence of adverse effects.1 2 4

  • Withdraw gradually to minimize potential for increased seizure frequency.1 59 In seizure studies, daily dosages were decreased in weekly intervals by 50–100 mg in adults and over a 2–8 week period in pediatric patients.1 59 In migraine studies, daily dosages were decreased in weekly intervals by 25–50 mg.1 59 (See Discontinuance of Therapy under Cautions.)

  • Closely monitor for notable changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.1 68 69 80 (See Suicidality Risk under Cautions.)

Administration

Oral Administration

Administer orally without regard to meals.1 2 4

Capsule/sprinkle formulation is bioequivalent to immediate-release tablet and may be substituted as a therapeutic equivalent.1

Capsules

Swallow capsules whole.1

Alternatively, open capsule and sprinkle entire contents on soft food (e.g., applesauce, custard, ice cream, oatmeal, yogurt, pudding); swallow immediately without chewing.1 24

Drinking fluids immediately may help to ensure that all of the mixture is swallowed.1

Do not store the sprinkle/food mixture for use at a later time.1

Tablets

Tablets preferably should be swallowed intact and not broken or chewed because of the bitter taste.1 2 4 24

If patient has difficulty in swallowing tablets, the tablets may be crushed and mixed with oatmeal or applesauce; use immediately since stability cannot be ensured.24

If tablets are broken, use immediately since stability beyond a brief period cannot be ensured.24 Discard any unused portion.24

Dosage

Pediatric Patients

Seizure Disorders
Monotherapy of Partial Seizures or Primary Generalized Tonic-Clonic Seizures

Children 2 to <10 years of age: Dosage recommendations in this population derived from pharmacokinetic and pharmacodynamic modeling data.1 Recommended initial dosage is 25 mg daily (administered nightly) for first week.1 Increase to 50 mg daily (administered as 25 mg twice daily) during second week if tolerated.1 Subsequently increase by 25–50 mg daily each week as tolerated.1 Attempt titration to minimum recommended dosage (see Table 1) over 5–7 weeks.1 May attempt additional increases (in increments of 25–50 mg daily at weekly intervals) up to maximum recommended dosage (see Table 1) based on tolerability and seizure control.1 Administer total daily dosage in 2 equally divided doses.1

Table 1. Target Maintenance Topiramate Dosages for Monotherapy of Partial Seizures or Primary Generalized Tonic-Clonic Seizures in Pediatric Patients 2 to <10 Years of Age1

Weight (kg)

Minimum Total Daily Dosage (mg/day)

Maximum Total Daily Dosage (mg/day)

Up to 11

150

250

12–22

200

300

23–31

200

350

32–38

250

350

>38

250

400

Children ≥10 years of age: Initially, 50 mg daily (administered as 25 mg twice daily).1 Titrate up to recommended dosage of 400 mg daily as tolerated according to schedule in Table 2.1 In clinical studies, approximately 58% of patients achieved the maximum dosage of 400 mg daily; mean dosage achieved was 275 mg daily.1

Table 2. Topiramate Dosage Titration Schedule for Monotherapy of Partial Seizures or Primary Generalized Tonic-Clonic Seizures in Pediatric Patients ≥10 Years of Age1

Morning Dose

Evening Dose

Week 1

25 mg

25 mg

Week 2

50 mg

50 mg

Week 3

75 mg

75 mg

Week 4

100 mg

100 mg

Week 5

150 mg

150 mg

Week 6

200 mg

200 mg

Adjunctive Therapy of Partial Seizures, Primary Generalized Tonic-Clonic Seizures, or Seizures Associated with Lennox-Gastaut Syndrome
Oral

Children 2–16 years of age: Initially, 25 mg (or less based on a range of 1–3 mg/kg daily) given nightly for the first week.1 Increase dosage at 1- or 2-week intervals in increments of 1–3 mg/kg daily, administered in 2 divided doses, to achieve optimal clinical response.1

Recommended maintenance dosage is approximately 5–9 mg/kg daily in 2 divided doses.1

Alternatively, some clinicians recommend an initial dosage of 0.5–1 mg/kg daily, with slow titration (in increments of 1–3 mg/kg every other week or in increments of 0.5–1 mg/kg per week) to obtain optimal efficacy with minimal adverse effects.33 36

Adults

Seizure Disorders
Monotherapy of Partial Seizures or Primary Generalized Tonic-Clonic Seizures
Oral

Initially, 50 mg daily (administered as 25 mg twice daily).1 Titrate up to recommended dosage of 400 mg daily as tolerated according to schedule in Table 3.1 In clinical studies, approximately 58% of patients achieved the maximum dosage of 400 mg daily; mean dosage achieved was 275 mg daily.1

Table 3. Topiramate Dosage Titration Schedule for Monotherapy of Partial Seizures or Primary Generalized Tonic-Clonic Seizures in Adults1

Morning Dose

Evening Dose

Week 1

25 mg

25 mg

Week 2

50 mg

50 mg

Week 3

75 mg

75 mg

Week 4

100 mg

100 mg

Week 5

150 mg

150 mg

Week 6

200 mg

200 mg

Adjunctive Therapy of Partial Seizures
Oral

Initially, 25–50 mg daily.1 2 4 24 Increase dosage at weekly intervals in increments of 25–50 mg to achieve optimal clinical response.1 2 4 24

Recommended maintenance dosage is 200–400 mg daily, administered in 2 equally divided doses (morning and evening).1 2 4 24

Limited data indicate that titration in increments of 25 mg/week is associated with a lower incidence of cognitive and psychiatric adverse effects and lower discontinuance rates24 41 but may delay the time to reach an effective dosage.1 24 41

Dosages >400 mg daily generally have not produced substantial additional improvement, but may improve seizure control in some patients, if tolerated.1 2 4 7 24 25

Adjunctive Therapy of Primary Generalized Tonic-Clonic Seizures
Oral

Initially, 25–50 mg daily.1 2 4 24 Increase dosage at weekly intervals in increments of 25–50 mg to achieve optimal clinical response.1 2 4 24

Recommended maintenance dosage is 400 mg daily, administered in 2 equally divided doses (morning and evening).1 2 4 24

Limited data indicate that titration in increments of 25 mg/week is associated with a lower incidence of cognitive and psychiatric adverse effects and lower discontinuance rates24 41 but may delay the time to reach an effective dosage.1 24 41

Seizures Associated with Lennox-Gastaut Syndrome
Oral

Manufacturer makes no specific dosage recommendations; in one controlled trial, topiramate was initiated at dosage of 1 mg/kg and titrated over 2 weeks to target dosage of approximately 6 mg/kg daily.1 24 85

Migraine Prophylaxis
Oral

Recommended total daily dosage is 100 mg, administered in 2 divided doses.1 Titrate therapy using the following schedule in Table 4.

Table 4. Topiramate Dosage Titration Schedule for Migraine Prophylaxis in Adults

Week

Morning Dose

Evening Dose

1

None

25 mg

2

25 mg

25 mg

3

25 mg

50 mg

4

50 mg

50 mg

Titrate dosage based on clinical outcome.1 Use longer intervals between dose adjustments if required.1

Alcohol Dependence

Optimum dosage regimen not established; initial dosage of 25 mg daily followed by gradual titration to maintenance dosage of 200–300 mg daily found to be effective in clinical studies.52 53 54 55 60 74 76 78 79

Clinical studies suggest that a more gradual titration (e.g., over 8 weeks) may be better tolerated than more rapid titration (e.g., over 6 weeks).52 55 74 76 77 78

A period of abstinence from alcohol prior to initiating topiramate therapy does not appear to be necessary.52 55 56 57 74 77 78

Optimum duration of therapy remains to be established; some clinicians recommend an initial period of at least 3 months to prevent relapse in alcohol-dependent patients, and possible continuation for ≥12 months if patient responds during this initial period.78

Prescribing Limits

Pediatric Patients

Monotherapy of Partial Seizures or Primary Generalized Tonic-Clonic Seizures
Oral

Children 2 to ≤10 years of age: Do not exceed maximum recommended maintenance dosage based on weight.1 (See Table 1.)

Adults

Adjunctive Therapy of Seizure Disorders
Oral

Dosages >1.6 g daily in patients with seizure disorders have not been studied.1 2 4

Special Populations

Hepatic Impairment

Clearance may be decreased; however, manufacturer makes no specific recommendations regarding dosage adjustment.1

Renal Impairment

If Clcr is <70 mL/minute per 1.73 m2, decrease daily adult dosage by 50%.1 2 4 Patients with renal impairment will require a longer time to reach steady state at each dosage level.1 2 4

Patients undergoing hemodialysis may require a supplemental dose following dialysis session; base amount on duration of dialysis, clearance rate of dialysis system, and the patient’s effective renal clearance of topiramate.1 2 4

Geriatric Patients

If Clcr <70 mL/minute per 1.73 m2, dosage adjustment may be necessary.1 85 (See Renal Impairment under Dosage and Administration.)

Cautions for Topamax

Contraindications

  • None.1

Warnings/Precautions

Warnings

Metabolic Acidosis

Hyperchloremic, non-anion gap, metabolic acidosis reported.1 24 43 (See Pediatric Use under Cautions.) Manifestations may include hyperventilation, nonspecific symptoms (e.g., fatigue, anorexia), cardiac arrhythmias, or stupor.1 43 Generally occurs early in therapy but can occur at any time.1 43

Potential for serious sequelae (e.g., nephrolithiasis, nephrocalcinosis, osteomalacia and/or osteoporosis with increased risk for fractures) from chronic, untreated metabolic acidosis.1 43

Measure serum bicarbonate concentrations at baseline and periodically during therapy.1 43 85

If metabolic acidosis develops and persists, consider reducing dosage or discontinuing therapy (by gradually tapering dose).1 43 If therapy is continued in patient with persistent acidosis, consider alkali treatment.1 43

Cognitive/Neuropsychiatric Effects

CNS-related adverse effects are common.1

Cognitive-related dysfunction (confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems), psychiatric/behavioral disturbances (e.g., depression, mood problems), somnolence, and fatigue associated with use in adults.1

Cognitive/neuropsychiatric events including psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems, and language problems reported in children, but with lower incidence compared with adults.1 Other neuropsychiatric effects reported in pediatric patients include somnolence, fatigue, headache, dizziness, and anorexia.1

Suicidality Risk

Increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).1 68 69 80 85 Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.1 68 69 85 Relative risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1 68 85

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.1 68 69 80 85 Anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality.1 68 85

Balance risk of suicidality with risk of untreated illness.1 68 85 Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.1 85 If suicidal thoughts or behavior emerges during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.1 85 (See Advice to Patients.)

Discontinuance of Therapy

Discontinue drug gradually to minimize the potential for increased seizure frequency.1 59 Appropriate monitoring recommended if more rapid withdrawal required.1 59 85

Ocular Effects

Acute myopia with secondary angle-closure glaucoma reported.1 Symptoms (e.g., acute onset of decreased visual acuity and/or ocular pain) typically occur within 1 month of initiating therapy.1

If adverse ocular signs or symptoms are detected, discontinue topiramate immediately and institute appropriate measures.1

Oligohidrosis and Hyperthermia

Possible oligohidrosis and hyperthermia, particularly in pediatric patients; rarely may require hospitalization.1 42

Monitor patients, particularly pediatric patients, closely for decreased sweating and increased body temperature, particularly in warm or hot weather.1 85 Ensure proper hydration before and during exercise or exposure to warm temperatures.42

Consider risk of hyperthermia when used concomitantly with other drugs that predispose to heat-related disorders.1 (See Drugs Predisposing to Heat-related Disorders under Interactions.)

Hypothermia with Concomitant Use of Valproic Acid

Hypothermia, with or without hyperammonemia, reported in patients receiving concurrent topiramate and valproic acid therapy.1 Can occur after initiating topiramate therapy or following dosage increase.1 Manifestations may include lethargy, confusion, coma, or substantial alterations in other major organ systems (e.g., cardiovascular, respiratory).1

If hypothermia occurs, consider discontinuance of topiramate or valproic acid.1 Since hypothermia also may be a manifestation of hyperammonemia, monitor plasma ammonia concentrations as part of clinical management.1

Sudden, Unexplained Deaths in Epilepsy

Higher incidence of sudden and unexplained deaths than would be expected in a healthy (nonepileptic) population; however, incidence is within range of estimates for patients with epilepsy or refractory epilepsy.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 81 82 (See Pregnancy under Cautions.) Increased risk of oral cleft birth defects (cleft lip and/or palate) reported with exposure during first trimester.1 81 82

Developmental toxicity, including teratogenicity and embryotoxicity, structural malformations, and maternal toxicity demonstrated in animals.1

Hyperammonemia and Encephalopathy

Hyperammonemia, with or without encephalopathy, reported in adults and pediatric patients receiving topiramate (with or without concomitant valproic acid).1 In some cases, ammonia concentrations were markedly increased (i.e., ≥50% above ULN).1

Appears to be more common when topiramate is used concomitantly with valproic acid.1 Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at increased risk.1

Manifestations of hyperammonemic encephalopathy include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting.1 In most cases, manifestations abated following discontinuance of either topiramate or valproic acid.1

If unexplained lethargy, vomiting, or changes in mental status occur, consider possibility of hyperammonemic encephalopathy and measure ammonia concentration.1

Kidney Stones

Increased incidence (1.5%) of kidney stone formation in clinical trials in adults; incidence higher in men than women.1 Kidney stones also reported in children 2–16 years of age.1

Avoid use in patients receiving other carbonic anhydrase inhibitors and in those on ketogenic diet.1

Maintain adequate fluid intake to decrease stone formation.1

Paresthesia

Common adverse effect; often associated with other carbonic anhydrase inhibitors.1

Laboratory Changes

Serum electrolyte abnormalities, including hypokalemia, hypophosphatemia, and increased serum alkaline phosphatase concentrations, reported.1 59 Clinical importance of these abnormalities not clearly established.1

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescription; similarity in spelling between Topamax (topiramate) and Toprol-XL (a trade name for metoprolol succinate, a β-adrenergic blocking agent) may result in errors.47 48 49 50 These medication errors have been associated with serious adverse events sometimes requiring hospitalization as a result of either lack of the intended medication (e.g., seizure or hypertension recurrence) or exposure to the wrong drug (e.g., bradycardia in a patient erroneously receiving metoprolol).47 48 49 50

Specific Populations

Pregnancy

Category C.1

Risk of fetal harm.1 81 82 (See Fetal/Neonatal Morbidity and Mortality under Cautions.) Use during pregnancy only if potential benefits outweigh possible risks.1 If used during pregnancy or if patient becomes pregnant while receiving the drug, apprise of potential fetal hazard.1

Carefully consider benefits versus risks in women of childbearing potential, particularly when topiramate is used for conditions not usually associated with permanent injury or death.1 81 If use is necessary in a woman of childbearing potential, advise patient to use effective contraception if not planning a pregnancy; consider alternative therapies in women who are planning a pregnancy.1 81

Effect of topiramate-induced metabolic acidosis not specifically studied during pregnancy; however, metabolic acidosis during pregnancy is known to cause decreased fetal growth, decreased fetal oxygenation, and fetal death.1 Monitor pregnant women for metabolic acidosis in the same manner as nonpregnant patients.1 In addition, monitor neonates since possible drug transfer and transient metabolic acidosis may occur following birth.1

North American Antiepileptic Drug Pregnancy Registry at 888-233-2334 or http://www.aedpregnancyregistry.org.1

Lactation

Distributed into human milk.1 81 Exercise caution when used in nursing women.1 81

Pediatric Use

Safety and efficacy for management of seizure disorders not established in children <2 years of age.1 2 Safety and efficacy for migraine prophylaxis not established in pediatric patients.1

Hyperchloremic, non-anion gap, metabolic acidosis reported.1 43 (See Metabolic Acidosis under Cautions.)

Cases of moderately severe metabolic acidosis reported in infants as young as 5 months of age, especially at dosages >5 mg/kg daily.1 Metabolic acidosis in patients <2 years of age (not an FDA-labeled population) notably greater in magnitude than that observed in older children and adults.1 Potential for serious sequelae (e.g., osteomalacia [rickets], reduced growth rates, decrease in maximal height achieved) resulting from chronic, untreated metabolic acidosis.1 43

Measure serum bicarbonate concentrations at baseline and periodically during therapy.1 43

Incidence of adverse nervous system effects appears to be lower in children than adults.1

Oligohydrosis and hyperthermia typically reported in children.1 42 (See Oligohidrosis and Hyperthermia under Cautions.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1

Clearance may be decreased in patients with reduced renal function.1 2 (See Special Populations under Pharmacokinetics.) Monitor renal function.1 85

Dosage adjustment may be necessary in geriatric patients with impaired renal function.1 (See Special Populations under Dosage and Administration.)

Hepatic Impairment

Clearance may be decreased; use with caution.1

Renal Impairment

Clearance decreased; dosage adjustment recommended for adults.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Adults receiving dosages of 50–200 mg daily (for migraine prophylaxis): paresthesia, fatigue, infection, taste perversion, nausea, anorexia, diarrhea, dizziness, weight loss, somnolence, difficulty with memory, difficulty with concentration/attention, sinusitis.1

Adults receiving dosage of 400 mg daily (for monotherapy of seizure disorders): paresthesia, weight loss, anorexia, somnolence, difficulty with memory.1

Children 6 to <16 years of age receiving dosage of 400 mg daily (for monotherapy of seizure disorders): fever, weight loss, mood problems, cognitive problems, infection, flushing, paresthesia.1

Adults receiving dosages of 200–400 mg daily (for adjunctive management of seizure disorders): somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia, diplopia.1

Adults receiving dosages of 200–1000 mg daily (for adjunctive management of seizure disorders): fatigue, nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, anxiety, mood problems, weight loss.1

Children 2–16 years of age receiving dosages of 5–9 mg/kg daily (for adjunctive management of seizure disorders): fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, weight loss.1

Adults receiving dosages ≤300 mg daily for alcohol dependence: paresthesia, taste perversion, fatigue, anorexia, insomnia, concentration and attention difficulties, memory impairment, nervousness, somnolence, diarrhea, dizziness, pruritus.52 54 55 60 74 78

Interactions for Topamax

Mild inhibitor of CYP2C19 and mild inducer of CYP3A4.1

Does not inhibit CYP1A2, 2A6, 2B6, 2C9, 2D6, 2E1, or 3A4/5.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions with drugs metabolized by CYP2C19 or CYP3A4 are possible.1

Drugs Predisposing to Heat-related Disorders

Potential pharmacologic interaction (increased risk of hyperthermia) with drugs that predispose to heat-related disorders (e.g., carbonic anhydrase inhibitors, drugs with anticholinergic activity); use with caution.1

Specific Drugs

Drug

Interaction

Comments

Amitriptyline

Increased plasma amitriptyline concentrations1

Adjust amitriptyline dosage based on patient’s clinical response, not on plasma amitriptyline concentrations1

Carbamazepine

Decreased plasma concentrations of topiramate1

Dosage adjustment of topiramate may be required when carbamazepine is added or withdrawn during adjunctive therapy1

Carbonic anhydrase inhibitors (e.g., acetazolamide, dichlorphenamide, zonisamide)

Possible increased risk or severity of metabolic acidosis and kidney stone formation; possible increased risk of hyperthermia1

Monitor for onset or worsening of metabolic acidosis1

CNS depressants (including alcohol)

Potential for enhanced CNS depression1

Use with extreme caution1

Digoxin

Possible decrease in serum digoxin concentrations1

Clinical importance unknown1

Dihydroergotamine

Pharmacokinetic interaction unlikely1

Diltiazem

Possible decreased plasma diltiazem concentrations and increased topiramate concentrations1

Glyburide

Possible decrease in plasma glyburide concentrations1

Haloperidol

No effect on pharmacokinetics of haloperidol1

Hydrochlorothiazide

Possible increased plasma topiramate concentrations; pharmacokinetics of hydrochlorothiazide not substantially altered1

Enhanced risk of hypokalemia1

Although clinical importance of this interaction not known, topiramate dosage adjustment may be necessary when hydrochlorothiazide is initiated1

Lamotrigine

Decreased plasma topiramate concentrations; lamotrigine concentrations not likely to be affected by concurrent administration of up to 400 mg daily of topiramate1 59 71 72

Lithium

Possible increased exposure to lithium with concurrent administration of high-dose (up to 600 mg daily) topiramate1

Monitor serum lithium concentrations in patients receiving concurrent lithium and high-dose topiramate therapy1

Metformin

Possible increase in plasma metformin concentrations;1 possible decrease in topiramate clearance1

Clinical importance of these pharmacokinetic effects unknown; however, topiramate can cause metabolic acidosis, a condition for which the use of metformin is contraindicated1

Oral contraceptives

Substantial decrease in ethinyl estradiol exposure reported in patients receiving an oral contraceptive containing ethinyl estradiol and norethindrone in conjunction with topiramate and valproic acid1

Consider possibility of decreased oral contraceptive efficacy and breakthrough bleeding 1

Phenobarbital

<10% change in plasma concentrations of phenobarbital1

Phenytoin

Possible increase in serum phenytoin concentrations (generally in those receiving twice-daily phenytoin regimen); decreased plasma topiramate concentrations1

Adjustment of phenytoin or topiramate dosage may be required during concomitant therapy1

Pioglitazone

Decreased systemic exposure to active metabolites of pioglitazone; however, clinical importance not known1

When topiramate therapy is initiated in patients receiving pioglitazone or vice versa, monitor blood glucose control carefully1

Primidone

<10% change in plasma concentrations of primidone1

Propranolol

Pharmacokinetic interaction unlikely1

Risperidone

Decreased plasma risperidone concentrations; increased plasma topiramate concentrations1

No clinically important changes observed1

Sumatriptan

No effect on pharmacokinetics of sumatriptan1

Valproic acid

Possible decrease in plasma concentrations of valproic acid and topiramate1

Concomitant use associated with hyperammonemia with or without encephalopathy; also associated with hypothermia (with or without hyperammonemia)1

Consider discontinuance of topiramate or valproic acid if hypothermia occurs1 85

Venlafaxine

Pharmacokinetics of venlafaxine or topiramate not affected1

Topamax Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration, with peak plasma concentrations achieved in about 2 hours.1

Capsule/sprinkle formulation is bioequivalent to immediate-release tablet.1

Food

Food does not affect bioavailability.1 46

Distribution

Extent

Appears to cross the placenta.45

Distributes into breast milk.45

Plasma Protein Binding

Approximately 15–41%.1 Fraction bound decreases with increasing plasma topiramate concentrations.1

Elimination

Metabolism

Not extensively metabolized.1 Six minor metabolites identified; none constitutes more than 5% of administered dose.1

Elimination Route

Eliminated principally in urine as unchanged drug (approximately 70%).1

Half-life

21 hours.1 46

Special Populations

In pediatric patients, clearance is 50% higher, resulting in a shorter elimination half-life and lower plasma concentrations, relative to adults.1

In geriatric patients with reduced renal function (Clcr reduced by 20% compared with younger adults), clearance was decreased.1 85

In patients with hepatic impairment, clearance may be decreased; mechanism not fully understood.1

In patients with moderate or severe renal impairment, clearance is reduced by 42 or 54%, respectively.1 85 In patients undergoing hemodialysis, clearance is 4–6 times more rapid than in healthy individuals.1 2 4 85

Stability

Storage

Oral

Capsules

Tight containers at ≤25°C.1 Protect from moisture.1

Tablets

Tight containers at 15–30°C.1 Protect from moisture.1

Actions

  • Mechanism of action is unknown; however, properties that may contribute to anticonvulsant and antimigraine activities, including blocking sodium channels, enhancing the inhibitory action of GABA by acting at some subtypes of GABA-A receptor, antagonizing AMPA/kainate subtype of glutamate receptor, and inhibiting carbonic anhydrase enzymes have been demonstrated in electrophysiologic and biochemical studies.1 2 4 15 16 17 18 19

  • Precise mechanism of action in alcohol dependence unknown; however, properties that may result in suppression of mesocorticolimbic dopaminergic activity include potentiation of GABA-mediated inhibitory neurotransmission and inhibition of glutamate-mediated neuroexcitation.1 52 54 55 57 58 60 61 62 63 64 74 75 77 78

Advice to Patients

  • Importance of taking topiramate exactly as prescribed.1 Importance of not abruptly discontinuing therapy.1

  • Importance of seeking immediate medical attention if blurred vision or periorbital pain develops.1

  • Importance of maintaining adequate fluid intake, particularly in patients with predisposing factors, to minimize the risk of kidney stone formation.1

  • Importance of considering an increase in food intake if patient is losing weight while taking topiramate.1

  • Importance of reviewing the manufacturer’s patient information for instructions regarding administration of the capsule/sprinkle formulation.1

  • Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.1 Patients with seizure disorders may continue to experience unpredictable seizures even when taking topiramate.1 59 85 Exercise caution when engaging in any activities where loss of consciousness could result in serious danger (e.g., swimming, driving a motor vehicle, climbing high places); avoidance of such activities altogether may be necessary in some patients.1 59 85

  • Risk of suicidality (anticonvulsants may increase risk of suicidal thoughts or actions in about 1 in 500 people).1 68 69 80 85 Importance of patients, family members, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).1 68 85

  • Importance of monitoring for evidence of decreased sweating and increased body temperature, particularly in children during hot weather.1 42 Importance of proper hydration before and during exercise and exposure to warm temperatures.42

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Topiramate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

15 mg

Topamax Sprinkle

Janssen

Topiramate Sprinkle Capsules

25 mg

Topamax Sprinkle

Janssen

Topiramate Sprinkle Capsules

Tablets, film-coated

25 mg*

Topamax

Janssen

Topiramate Tablets

50 mg*

Topamax

Janssen

Topiramate Tablets

100 mg*

Topamax

Janssen

Topiramate Tablets

200 mg*

Topamax

Janssen

Topiramate Tablets

AHFS DI Essentials. © Copyright 2017, Selected Revisions May 1, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Janssen Pharmaceuticals. Topamax (topiramate) tablets and capsules prescribing information. Titusville, NJ: 2011 July.

2. Ortho-McNeil. Topamax (topiramate) clinical review. Raritan, NJ: undated.

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